Project Summary Obesity is the result of a chronic, relapsing progressive disease process that has become a global pandemic. Reductions in weight as small as 5-10% drastically help reduce the comorbidities of obesity, however weight loss is extremely difficult to maintain. Anti-obesity drugs are promising interventions to help overcome the challenge of maintaining weight loss, yet most have been withdrawn due to serious side effects. For this reason, further research is needed on strategies for producing sustained weight loss. One drug class currently being tested in clinical trails, methionine aminopeptidase 2 (MetAP2) inhibitors, rapidly reduce body weight, increase glycemic control, and reduce serum lipids. Remarkably, clinical trials with MetAP2i are ongoing despite the fact we know little about how MetAP2 mediates anti-obesogenic effects. In vitro studies have shown that MetAP2 is a multifunctional protein that removes the N-terminal methionine residue from newly translated proteins, but can also directly impact major cell signaling pathways. In the past, it has been challenging to study the effects of MetAP2 expression in vivo, because the developmental models of MetAP2 elimination are embryonically lethal. To overcome this problem, we have generated mouse models that overexpress or knockdown MetAP2 in an inducible, tissue-specific manner. These mouse models will allow us to examine the systemic effects and molecular mechanisms of MetAP2 expression in two major peripheral organs that regulate glucose and lipid metabolism during obesity: liver and adipose tissue. Only after understanding the mechanisms that underlie the cellular effects of MetAP2, will we begin to understand how MetAP2 or MetAP2 inhibitors take part in the complex regulation of whole-body energy balance. Specifically, in Aim 1 we will determine whether MetAP2 expression in adipocytes and hepatocytes regulate body weight, energy expenditure, glucose tolerance, and serum lipid levels. The goal of Aim 2 is to examine whether the three known MetAP2 mechanisms discovered in vitro are found to be relevant to liver and adipose tissue lipid metabolism in vivo.